Robert Greenhouse

RS-127445: a selective, high affinity, orally bioavailable 5-HT2B receptor antagonist.

Efforts to define precisely the role of 5‐HT2B receptors in normal and disease processes have been hindered by the absence of selective antagonists. To address this deficiency, we developed a series of naphthylpyrimidines as potentially useful 5‐HT2B receptor antagonists. RS‐127445 (2‐amino‐4‐(4‐fluoronaphth‐1‐yl)‐6‐isopropylpyrimidine) was found to have nanomolar affinity for the 5‐HT2B receptor (pKi=9.5±0.1) and 1,000 fold selectivity for this receptor as compared to numerous other receptor and ion channel binding sites. In cells expressing human recombinant 5‐HT2B receptors, RS‐127445 potently antagonized 5‐HT‐evoked formation of inositol phosphates (pKB=9.5±0.1) and 5‐HT‐evoked increases in intracellular calcium (pIC50=10.4±0.1). RS‐127445 also blocked 5‐HT‐evoked contraction of rat isolated stomach fundus (pA2=9.5±1.1) and (±)α‐methyl‐5‐HT‐mediated relaxation of the rat jugular vein (pA2=9.9±0.3). RS‐127445 had no detectable intrinsic activity in these assays. In rats, the fraction of RS‐127445 that was bioavailable via the oral or intraperitoneal routes was 14 and 60% respectively. Intraperitoneal administration of RS‐127445 (5 mg kg−1) produced plasma concentrations predicted to fully saturate accessible 5‐HT2B receptors for at least 4 h. In conclusion, RS‐127445 is a selective, high affinity 5‐HT2B receptor antagonist suitable for use in vivo. The therapeutic potential of this molecule is being further evaluated.

Novel 3,3-disubstituted pyrrolidines as selective triple serotonin/norepinephrine/dopamine reuptake inhibitors

A series of 3,3-disubstituted pyrrolidine monoamine triple reuptake inhibitors were discovered. Analogues with low nanomolar potency, good human in vitro microsomal stability and in vitro permeability, and low drug-drug interaction potential are described. One example showed in vivo anti-depressant-like effects in the mouse tail suspension assay with a minimum effective dose of 30 mg/kg i.p.

Design, synthesis, and biological evaluation of new monoamine reuptake inhibitors with potential therapeutic utility in depression and pain

Two new series of monoamine triple reuptake inhibitors (TRIs) have been discovered through scaffold homologation of our recently reported series of 3,3-disubstituted pyrrolidine TRIs. The regioisomeric 2- and 3-ketopyrrolidines demonstrated high levels of potency against all three monoamine transporters as well as good human in vitro stability, low drug-drug interaction potential and a decreased propensity for hERG channel binding. Representative compounds from these series displayed good in vivo pharmacokinetics and high monoamine receptor occupancies which are indicators of good brain penetration.

RS 30026: a potent and effective calcium channel agonist

1 A series of dihydropyridine derivatives has been evaluated for calcium channel agonist activity using reversal of nisoldipine‐induced inhibition of beating of aggregates of embryonic chick myocytes. This test appears to be specific for calcium channel agonists since isoprenaline and cardiac glycosides are inactive. 2 RS 30026 was the most potent of the series, was significantly more potent than CGP 28392 and of similar potency to Bay K 8644 (pEC50 = 7.45, 6.16 and 7.20, respectively). RS 30026 increased edge movement of individual aggregates, in the absence of nisoldipine, by 50% at 2nm. 3 Compounds were also evaluated for their effects on guinea‐pig papillary muscle and porcine coronary artery rings. RS 30026 displayed positive inotropism at concentrations between 10−9 and 10−6 m (pEC200 = 8.21), but was a much more powerful inotrope than Bay K 8644, increasing contractility to 1300% of control at 10−6 m (compared to 350% of control for Bay K 8644). RS 30026 caused vasoconstriction at concentrations between 10−10 and 10−7 m. 4 Calcium channel currents in single embryonic chick myocytes were recorded by whole‐cell voltage clamp techniques. RS 30026 (100 nm‐500 nm) produced large increases in peak current amplitude and shifted the voltage for threshold and maximal currents to more negative values. RS 30026 (500 nm) also produced large increases in the inward tail currents evoked upon repolarization. The effects of Bay K 8644 (50 and 500 nm) were much less marked. 5 Analysis of the activation characteristics of currents showed parallel shifts in the activation curve to more negative potentials in the presence of 50 nm Bay K 8644, with a much smaller shift in the presence of 500 nm Bay K 8644. RS 30026 (100 and 500 nm) caused concentration‐dependent shifts in the activation of the calcium channel currents with an increase of the slope of the curve. 6 RS 30026 appears to be the most potent and effective calcium channel agonist described to date.